Side effect, main trouble

Even as links between a popular diabetes drug and bladder cancer surface, our national programme to track side effects of marketed drugs is all but under-sized.

Bandra resident Bihari Bajaj is worried about how his blood sugar levels will balance out in the coming week. The 68-year-old has been on the Pioglitazone tablet for four years after he was detected with type II diabetes in 2008. Yet, after the health ministry issued a ban on the drug on June 18 citing its link to an increased risk of bladder cancer, Bajaj has had to switch to another drug — Galvus MET.

Not only is this more expensive (Pioglit MF costs Rs 63 for a pack of 10 tablets; Galvus MET 50/500 costs Rs 215), it is also not as efficient as Pioglitazone, or Pio for short. The latter is widely acknowledged as a wonder drug, as it keeps blood glucose levels in check. Known side effects of Pio include water retention and congestive heart failure and doctors only prescribe it for continuous intake if these aren't manifested in the patient. Bajaj, who underwent an angioplasty 15 years ago, has had no complaints.

With the second-highest population of diabetics globally, India has seen Pio become a much vaulted weapon in the arsenal of diabetologists. According to DG Shah, secretary general of the Indian Pharma Alliance, over 30 lakh diabetics in the country are on it.

In a twist to the controversy, however, news reports on Friday said the ban will be revoked temporarily, till the Drug Technical Advisory Board, scheduled to meet later this month, offers its verdict. Sources in the ministry told Mirror last week that an expert committee appointed to study the ban argued against it. The drug will soon be made available, but only to those with existing prescriptions, sources added.

Yet the story doesn't end there. In fact, here's where it begins.

Side effects sidetracked There is little evidence of what Pio has done to Indian patients, simply because there has been no system to track the drug's adverse reactions (ADRs) since it was first introduced over a decade ago. In contrast, France banned Pio in June 2011 based on an epidemiological study conducted in the country. The following day, Germany followed suit. The United States Food and Drugs Administration (USFDA) however, chose not to ban the drug, but announced that it be sold with a warning instead. The ban in India is not based on local data — something that even detractors of the drug, like Dr V Mohan, president of Research Society for Study of Diabetes in India, find problematic.

The Chennai-based diabetologist is keen to remain neutral on the "Pioglitazone controversy" although he collected eight cases of patients who developed bladder cancer after being administered the drug for periods ranging from two to nine years.

His report published in the Journal of Association of Physicians of India exhorted "extreme caution" in the drug's usage and noted that "a nationwide pharmacovigilance study appears to be justified to see (...) whether these cases are just sporadic ones, or whether they represent the tip of the iceberg."

"France, Germany and the US make these decisions because they have a mechanism in place to observe side effects long after the drug has been in the market. We, too, need to have an accurate system of reporting and identifying side effects to protect patients. After all, no patient should be harmed due to a drug," says Dr Mohan.

Dr GN Singh, the Drugs Controller General of India who is responsible for approval of licences of specified categories of drugs, admits that the ban was based on international reports. "The USFDA has a robust drug monitoring system with a dedicated staff of 14,000 (people). We have a core team of 350. We are relying on an international database only because we do not have our own ADR reports."

However, that may soon change.

Building a plan The practise of tracking side effects and benefits of drugs in the market is called pharmacovigilance (PV) — many countries around the world follow it. China, for instance, reported 6.9 lakh ADRs in 2010 alone. In India, the national PV programme has seen many fits and starts.

The Indian Council of Medical Research established a multi-centric reporting system in 1989 and a Taskforce Project in 1992. Between 1998 and 2005, when a WHO-sponsored and World Bankfunded National Pharmacovigilance Programme was launched, India had reported barely 400 ADRs to WHO's database. Under the new programme, 25 peripheral centres were nominated, one of them being the BJ Medical College in Ahmedabad. A memorable report published in 2008 in the Indian Journal of Pharmacology, titled Pleasures and pains of running a pharmacovigilance centre, talked of the apathy and lack of awareness among drug prescribers that made it difficult to carry out the task of collecting and reporting ADRs. Soon, funding dried up, and the programme came to a halt.

Then, in 2010, it was revived, this time under the aegis of the Ministry of Health and Family Welfare, coordinated by the Indian Pharmacopoeia Commission (IPC). The National Co-Ordination Centre for monitoring ADRs runs what is now called the Pharmacovigilance Programme of India (PvPI), helmed by Dr Singh. Already, 90 public and private medical colleges with hospitals work as monitoring centres, and feed data directly into the WHO database. According to the IPC website, a five-year target is in place to expand the number of monitoring centres and make India a centre of excellence in pharmacovigilance by 2015.

"At last count we have received 54,000 ADRs," Dr Singh says, but admits that the data has to be analysed for India-specific situations.

"We monitor international drug alerts and plan to set up a panel of experts to study information from our ADR centres. We propose to have ADR monitoring centres in 365 medical colleges with hospitals. We are looking for support of corporate houses. Once we have a panel, we should be able to have regulatory authority on drug sale and use. Then we would be sending out drug alerts and the rest of the world will track us," he says.

Down to brass tacks Dr Urmila Thatte, head of the clinical pharmacology department at KEM hospital, Parel — one among 90 ADR monitoring centres — says the involvement of private medical practitioners is essential for this programme to work. Most of the centres are public institutions where the drugs used are not always new, and their side effects are well-known. In contrast, newer drugs are sold more aggressively to private doctors, and that's where information is most lacking. Pio, for instance, is not commonly prescribed in public health centres.

While pharmaceutical companies are mandated by law to submit a Periodic Safety Update Report (PSURs) for four years after the drug enters the market, few do. Last year, a parliamentary standing committee selected 42 drugs at random and found no PSURs for 17. A newsletter published by the PvPI in April also noted, "Manufacturers do not submit the required PSURs even years after getting approval from the regulatory authority. Therefore, assessment of safety and efficacy of such new drugs in post marketing scenario remains incomplete."

ADR reporting also depends on voluntary submission by doctors. An attitude shift is essential to ensure this, says Dr Thatte. "There are a number of reasons that prevent doctors from reporting side effects, such as the fear of being implicated if an adverse reaction is noted, lack of time and knowledge about reporting centres, or even incomplete communication by their patient," she says.

Perhaps to address this, the ADR form available on the IPC website states in bold red letters that "submission of a report does not constitute an admission that medical personnel or manufacturer or the product caused or contributed to the reaction."

Further, pharma companies often send representatives to doctors to get feedback about their drugs. A spokesperson from Sun Pharma says, "Sun Pharma has submitted a fairly large number of PSURs to DCGI. We have implemented a system, wherein all new approvals by DCGI and subsequent launches are tracked on a realtime basis." They also pointed out that drugs approved by the Food and Drugs Administrator of a state needn't be tracked, as per rules. However, when we asked them about how many of their drugs have received state FDA approvals and how many PSURs have they submitted, we received no answers.

Dr Manoj Chawla, a consultant diabetologist at the Asian Heart Institute, points out that a number of side effects are made visible during the clinical trials of drugs. But there is no law which mandates that internal PV records be shared with the national programme. And pharma companies don't always take clinical trials seriously. In April, a parliamentary standing committee found that 33 new drugs were approved between January 2008 and October 2010 without conducting clinical trials on Indian patients.

Gauri Kamath, a journalist who has tracked the pharma and healthcare industry for 15 years, sounds the end note.

"It is not as if good work isn't being done," says the founder of Apothecurry, a blog that comments on both industries. "In the last six months, the programme has been able to aid India's drug regulator by sharing India-specific ADR reports on drugs such as painkiller Analgin, diabetes drug Pioglitazone and muscle relaxant Tolperisone. The IPC also puts up newsletters on its websites that have data on the drugs it is tracking. The main shortcoming of course, is that this is by no means enough. The programme scale is still undersized for a country like India."

Kamath says that no one sector is responsible —"We live in a culture where health isn't taken seriously. Everybody, from the patient to the centre needs to be invested in this." — With Lakshmi Iyer in Delhi